Lyme disease is a multisystem illness caused by infection with the spirochete Borrelia burgdorferi and it is the leading vector-borne disease in the United States. Lyme disease is also common in Europe and also occurs in Russia, China and Japan. In humans, B. burgdorferi infection causes infection primarily in the skin, nervous system, heart and joints. Lyme disease can usually be treated successfully with antibiotic therapy, with the best results seen in patients with early disease. Unfortunately, some patients may not have a complete response to therapy. We currently have three clinical protocols studying patients with Lyme disease. Two protocols are natural history studies and serve as the basis for multiple lines of investigation. One protocols addresses patients with post treatment Lyme disease syndrome. The other protocol allow for the study of patients with classical Lyme disease. A third protocol will examine the host reponse in skin biopsies from patients with erythema migrans lesions using microarrays. Our work addresses 3 areas in Lyme disease: laboratory diagnosis, clinical manifestations and immunological responses to B. burgdorferi.